UTI remain a common and serious clinical problem that affect 10-15 percent of all women in their lifetime. Women seeking treatment for acute UTI account for over 5 million visits to physician's offices annually in the United States. Health care costs to treat only uncomplicated lower tract infections are nearly one billion dollars per year. The most accepted hypothesis for the pathophysiology of ascending UTI in susceptible women is that uropathogens carried in the fecal flora sequentially colonize the vaginal introitus, urethra, bladder, and finally the kidneys. E. coli strains are responsible for the majority of UTIs and have specific virulence factors such as adhesins for uroepithelial cell receptors, certain O and K antigens, and hemolysins. The reasons for increased susceptibility of female children and certain adult women are unknown but may be due to increased binding of E. coli to epithelial cells lining the vagina and bladder in conjunction with decreased levels of urinary antibody to infecting organisms. The roles of immune defects in UTI have not been comprehensively studied, although immunologic hyporesponsiveness in UTI may be a critical and heretofore undefined factor in explaining susceptibilities. The author's work with animal models of increased susceptibility to UTI has shown that: 1) severe T and B cell deficiencies decrease the ability of mice to resolve an infection; 2) induced hyporesponsiveness to E. coli in monkeys leads to poor resolution of an E. coli UTI; 3) increased levels of serum and urinary anti E. coli antibody correlate with early resolution of an E. coli UTI; 4) inbred mouse strains have variable susceptibility to an E. coli UTI; and 5) the specificities of anti E. coli antibodies produced in mice correlate with susceptibility to UTI. Studies of patients with recurrent UTI's have shown that they have different patterns of antibody responses to E. coli antigens than nonsusceptible women and different frequencies of some major histocompatibility antigens. The proposed research will focus on defining an immunogenetic basis of susceptibility to UTIs. It will: 1) define the nature and role of genetically determined immunodeficiency in murine UTI susceptibility; 2) determine the role of acquired immunologic hyporesponsiveness in development of UTIs; and 3) investigate the heritability of susceptibility to UTIs.